The fork protection complex promotes parental histone recycling and epigenetic memory.

Autor:	Charlton SJ; Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Flury V; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Kanoh Y; Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan., Genzor AV; Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark., Kollenstart L; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Ao W; Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark., Brøgger P; Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark., Weisser MB; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Adamus M; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Alcaraz N; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Delvaux de Fenffe CM; Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, The Netherlands., Mattiroli F; Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht, The Netherlands., Montoya G; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark., Masai H; Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan., Groth A; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark; Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark; Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: anja.groth@cpr.ku.dk., Thon G; Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: gen@bio.ku.dk.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Sep 05; Vol. 187 (18), pp. 5029-5047.e21. Date of Electronic Publication: 2024 Aug 01.
DOI:	10.1016/j.cell.2024.07.017
Abstrakt:	The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator of symmetric parental histone inheritance. Mrc1 mutants in a key connector domain disrupted segregation of parental histones to the lagging strand comparable to Mcm2 histone-binding mutants. Both mutants showed clonal and asymmetric loss of H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning of H3-H4 tetramers by Mrc1 and Mcm2, with the Mrc1 connector domain bridging histone and Mcm2 binding. Biochemical and functional analysis validated this model and revealed a duality in Mrc1 function: disabling histone binding in the connector domain disrupted lagging-strand recycling while another histone-binding mutation impaired leading strand recycling. We propose that Mrc1 toggles histones between the lagging and leading strand recycling pathways, in part by intra-replisome co-chaperoning, to ensure epigenetic transmission to both daughter cells. Competing Interests: Declaration of interests A.G. is co-founder and chief scientific officer (CSO) of Ankrin Therapeutics. A.G. is a member of the scientific advisory board of Molecular Cell. G.M. is a stockholder of Ensoma and a member of its scientific advisory board. The other authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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